Changes in readthrough acetylcholinesterase expression modulate amyloid-beta pathology.

Détails

ID Serval
serval:BIB_3D1467FC140B
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Changes in readthrough acetylcholinesterase expression modulate amyloid-beta pathology.
Périodique
Brain
Auteur(s)
Berson A., Knobloch M., Hanan M., Diamant S., Sharoni M., Schuppli D., Geyer B.C., Ravid R., Mor T.S., Nitsch R.M., Soreq H.
ISSN
1460-2156 (Electronic)
ISSN-L
0006-8950
Statut éditorial
Publié
Date de publication
01/2008
Peer-reviewed
Oui
Volume
131
Numéro
Pt 1
Pages
109-119
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
Publication Status: ppublish
Résumé
Alzheimer's disease has long been known to involve cholinergic deficits, but the linkage between cholinergic gene expression and the Alzheimer's disease amyloid pathology has remained incompletely understood. One known link involves synaptic acetylcholinesterase (AChE-S), shown to accelerate amyloid fibrils formation. Here, we report that the 'Readthrough' AChE-R splice variant, which differs from AChE-S in its 26 C-terminal residues, inversely exerts neuroprotective effects from amyloid beta (Abeta) induced toxicity. In vitro, highly purified AChE-R dose-dependently suppressed the formation of insoluble Abeta oligomers and fibrils and abolished Abeta toxicity to cultured cells, competing with the prevalent AChE-S protein which facilitates these processes. In vivo, double transgenic APPsw/AChE-R mice showed lower plaque burden, fewer reactive astrocytes and less dendritic damage than single APPsw mice, inverse to reported acceleration of these features in double APPsw/AChE-S mice. In hippocampi from Alzheimer's disease patients (n = 10), dentate gyrus neurons showed significantly elevated AChE-R mRNA and reduced AChE-S mRNA. However, immunoblot analyses revealed drastic reductions in the levels of intact AChE-R protein, suggesting that its selective loss in the Alzheimer's disease brain exacerbates the Abeta-induced damages and revealing a previously unforeseen linkage between cholinergic and amyloidogenic events.
Mots-clé
Acetylcholinesterase/genetics, Acetylcholinesterase/pharmacology, Acetylcholinesterase/physiology, Adult, Aged, Aged, 80 and over, Alternative Splicing, Alzheimer Disease/enzymology, Alzheimer Disease/metabolism, Alzheimer Disease/pathology, Amyloid beta-Peptides/antagonists & inhibitors, Amyloid beta-Peptides/biosynthesis, Amyloid beta-Peptides/drug effects, Animals, Astrocytes/pathology, Brain/metabolism, Brain/pathology, Dendrites/pathology, Dose-Response Relationship, Drug, Female, Gene Expression Regulation, Enzymologic, Hippocampus/enzymology, Humans, Male, Mice, Mice, Transgenic, Middle Aged, RNA, Messenger/genetics, Recombinant Proteins/pharmacology, Tumor Cells, Cultured
Pubmed
Web of science
Open Access
Oui
Création de la notice
25/05/2018 9:44
Dernière modification de la notice
20/08/2019 14:33
Données d'usage